Therapeutic or preventive agent for meibomian gland dysfunction or meibomian gland blockage

ABSTRACT

The objective of the present invention is to provide a new medicinal use of clarithromycin. The present invention is a therapeutic agent or a preventive agent for meibomian gland dysfunction or meibomian gland blockage and comprises clarithromycin as an active ingredient. The dosage form is preferably an eye drop or eye ointment.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a continuation application of U.S. patentapplication Ser. No. 14/670,999, filed on Mar. 27, 2015, the entirecontents of which are incorporated herein by reference and priority towhich is hereby claimed. application Ser. No. 14/670,999 is the U.S.National stage of application No. PCT/JP2012/075119, filed on Sep. 28,2012, the disclosure of which is also incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to a therapeutic or preventive

agent for meibomian gland dysfunction or meibomian gland concretion.

BACKGROUND ART

There are approximately 25 meibomian glands in the upper eyelid andapproximately 20 meibomian glands in the lower eyelid of the human eye,and lipids are secreted from the meibomian gland orifices. Meibomiangland dysfunction (MGD) is a condition where a diffuse abnormality ofthe function of the meibomian glands is induced by various causes, andis accompanied by chronic ocular discomfort. Further, meibomian glandconcretion is a condition where meibomian glands are obstructed by awhite non-opaque oily clot formed in the duct because of decreasedmeibomian gland function.

On the other hand, clarithromycin is a macrolide antibiotic, which hasbeen used for therapy of pharyngitis, tonsillitis, pneumonia, skininfections, acute exacerbation of chronic bronchitis and the like basedon its antibacterial effect. Recently, aside from antibacterial effects,clarithromycin has been found to have antiinflammatory,immunoregulatory, and anti-bacterial biofilm effects, and based on thesenovel effects, starting with the therapy of endometriosis or fibroids,gastrointestinal disorders, and pruritus, the use of clarithromycin hasalso been proposed for acute exacerbation of chronic bronchitis,bronchial asthma, influenza virus infection, atopic dermatitis,rheumatoid arthritis, etc. (Patent Publications 1, 2, and 3).

Patent Document 1: Japanese Unexamined Patent Application, PublicationNo. 2006-241172

Patent Document 2: Japanese Unexamined Patent Application, PublicationNo. H06-92850

Patent Document 3: Japanese Unexamined Patent Application, PublicationNo. H11-147827

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

Thus, the investigation of novel medical applications of clarithromycinis a subject of great interest.

Means for Solving the Problems

The present inventors sought and diligently researched novel medicalapplications of clarithromycin, and discovered that (1) in tests ofmeibomian gland peripheral telangiectasia due to the administration ofcomplete Freund's adjuvant using rats, clarithromycin notably improvedthe telangiectasia score, and (2) in tests of obstruction meibomiangland orifices due to feeding an HR-AD diet using hairless mice,clarithromycin notably reduced the number of obstructions of themeibomian gland orifices, and improved the obstructions, and thuscompleted the present invention.

Namely, the present invention is therapeutic agent or preventive agentfor meibomian gland dysfunction or meibomian gland concretion comprisingclarithromycin as the effective component.

Effects of the Invention

Thus, it is expected that a formulation comprising clarithromycin as theeffective component will be effective for therapy or prevention ofmeibomian gland dysfunction or meibomian gland concretion.

PREFERRED MODE FOR CARRYING OUT THE INVENTION

Below, embodiments of the present invention are explained.

The clarithromycin of the present invention can be easily produced by aconventional method, or obtained commercially.

Meibomian gland dysfunction (MGD) is a condition where diffuseabnormality of the meibomian glands is induced by various causes, and isaccompanied with chronic ocular discomfort. Meibomian gland dysfunctioncan be categorized by a condition of the secretion of the meibomianglands, and can be divided into reduced secretion type and increasedsecretion type, and in clinical practice, the reduced secretion type ismore common than the increased secretion type.

Reduced secretion type meibomian gland dysfunction is a condition wherethe secretion of the meibomian lipid is reduced by the accumulation ofexcess keratinized substances in the duct of the meibomian gland, or bythe obstruction of the meibomian gland orifices by various causes.Finding of obstructions of the meibomian gland orifices or finding ofabnormalities surrounding the meibomian gland orifices (telangiectasia,displacement of the mucocutaneous junction, irregularity of the eyelidmargins, and the like) are considered to be pathognomic findings ofreduced secretion type meibomian gland dysfunction.

Increased secretion type meibomian gland dysfunction is a disorder wherelipid secretion of the meibomian glands is excessive, and has thecharacteristic that large quantities of meibomian gland lipids aredischarged to the eyelid margins in reaction to compression of thetarsus.

Meibomian gland concretion is a condition where a mixture of keratinizedsubstances and lipids is concreted in the duct of the meibomian gland,and obstruction of the orifice of the meibomian gland is considered as acharacteristic finding.

As induced symptoms accompanying meibomian gland dysfunction ormeibomian gland concretion, there are many symptoms such as oculardiscomfort, burning sensations, itching and the like.

The therapeutic agent or preventive agent for meibomian glanddysfunction or meibomian gland concretion of the present invention canbe administered orally or parenterally. As the dosage form, dosage formsfor parenteral use such as ophthalmic solutions, ophthalmic ointments,injections and the like, and dosage forms for oral administration suchas tablets, capsules, granules, powders and the like may be mentioned,and in particular, ophthalmic solutions are particularly preferable.

The formulation thereof can be carried out using generally usedtechniques. For example, in the case of an ophthalmic solution, atonicity agent such as sodium chloride or concentrated glycerin and thelike; a buffer such as sodium phosphate, sodium acetate and the like; asurfactant such as polyoxyethylene sorbitan monooleate, polyoxyl 40stearate, polysorbate 80, polyoxyethylene hydrogenated castor oil andthe like; a stabilizer such as sodium citrate or sodium edetate and thelike; and a preservative such as benzalkonium chloride, paraben and thelike; and the like may be used as needed. The pH may be within theallowable range of ophthalmic solutions, and is preferably in the rangeof 4 to 8.

In the case of an ophthalmic ointment, the formulation may be carriedout using a general purpose base such as white petrolatum, liquidparaffin, and the like.

In the case of oral preparations such as tablets, capsules, granules,powders and the like, the formulation may be carried out using anextender such as lactose, crystalline cellulose, starch, vegetable oiland the like; a lubricant such as magnesium stearate, talc and the like;a binder such as hydroxypropyl cellulose, polyvinyl pyrrolidone and thelike, a disintegrant such as carboxylmethyl cellulose calcium,low-substituted hydroxypropylmethyl cellulose and the like, a coatingagent such as hydroxypropylmethyl cellulose, macrogol, a silicon resinand the like; a film forming agent such as gelatin film and the like;and the like, as needed.

The dose of clarithromycin can be properly selected depending on thesymptoms, age, dosage form and the like, and in the case of anophthalmic solution, a formulation of from 0.0001 to 5% (w/v),preferably from 0.01 to 3% (w/v), may be dropped into the eye on theorder of from 1 to 6 times/day. In the case of an oral preparation,clarithromycin may be usually administered at from 0.1 to 5000 mg perday, preferably 1 to 1000 mg per day, at once or divided into severaldoses.

The present invention includes the following inventions.

(1) Clarithromycin for use in the therapy or prevention of MGD ormeibomian gland concretion.

(2) Clarithromycin as recited above in item (1) formulated as a dosageform of an ophthalmic solution or an ophthalmic ointment.

(3) Use of clarithromycin for manufacturing a medicament for therapy orprevention of MGD or meibomian gland concretion.

(4) The use as recited above in item (3) wherein the dosage form of themedicament is an ophthalmic solution or an ophthalmic ointment.

EXAMPLES

Hereinafter, preparation examples and results of pharmacological testsare shown, but these examples are to facilitate understanding of thepresent invention and do not limit the scope of the present invention.

Preparation Example 1

In 100 ml,

Clarithromycin 1 g

Concentrated glycerin 2 g

Dibasic sodium phosphate hydrate 0.1 g

Polyoxyl 40 stearate 0.1 g

Diluted hydrochloric acid/sodium hydroxide q.s.

Sterile purified water q.s.

pH 7.0

By altering the amount of clarithromycin to be added, solution-typeophthalmic solutions at concentrations of 0.01% (w/v), 0.1% (w/v) or1.0% (w/v) could be prepared.

Preparation Example 2

In 100 ml,

Clarithromycin 1 g

Sodium chloride 0.75 g

Disodium hydrogen phosphate 0.06 g

Sodium dihydrogen phosphate 0.6 g

Polysorbate 80 0.005 g

Hydroxypropyl methyl cellulose 0.001 g

Sodium edetate hydrate 0.01 g

Diluted hydrochloric acid/sodium hydroxide q.s.

Sterile purified water q.s.

pH 7.0

By altering the amount of clarithromycin to be added, suspension-typeophthalmic solutions at concentrations of 0.1% (w/v) or 0.5% (w/v) couldbe prepared.

Preparation Example 3

In 100 ml,

Clarithromycin 2 g

Liquid paraffin 30 g

White soft paraffin q.s.

By altering the amount of clarithromycin to be added, ophthalmicointments at concentrations of 1% (w/w) or 5% (w/w) could be prepared.

Pharmacological Tests

1. Test for Meibomian Gland Peripheral Telangiectasia by Administrationof Full Friend's Adjuvant Using Rats

(Method for Preparation of Test Sample)

Clarithromycin (LKT Laboratories, Inc.), concentrated glycerin, dibasicsodium phosphate hydrate and polyoxyl 40 stearate were added to purifiedwater and dissolved to prepare a test sample comprising clarithromycinat a final concentration of 1% (w/v), at pH 7.

(Test Method)

Twenty five μl of complete Freund's adjuvant was administered to onesite of the right upper eyelid of female Lewis rats at five weeks age.On the seventh day from the initiation, the periphery of the meibomiangland orifices on the right upper eyelid was observed using a slit-lampand a telangiectasia score was determined. The eyelid margin of theupper eyelid was divided into three segments: ear, middle and nasalsites, and based on criteria described in Table 1, scores oftelangiectasia peripheral to the meibomian gland orifices in eachsegment were determined and the sum of the scores in three segments werecalculated as the telangiectasia score of one eye. The presence orabsence of dilation of the capillaries was determined based on whether acapillary that is usually not visible could be ascertained as a resultof enlargement of the capillary diameter.

TABLE 1 Condition of telangiectasia in the vicinity of meibomian glandScore orifices 0 Dilation of the capillaries is not recognized at theperiphery of the meibomian gland orifices when eyelid is in openedstate. 1 Dilation of a few capillaries is recognized at the periphery ofthe meibomian gland orifices when eyelid is in opened state. 2 Moderatedilation of the capillaries or slight redness is visible at theperiphery of the meibomian gland orifices when eyelid is in openedstate. 3 Redness and severe telangiectasia are visible surroundingmeibomian gland orifices when eyelid is in opened state.

After dividing into a saline-administered group and a 1% (w/v)clarithromycin aqueous solution-administered groups, the test wascarried out with six eyes in each group so as to minimize variations inmean scores, and from the 8th day after initiation, saline (5 μl/eye,six times per day) or 1% (w/v) clarithromycin aqueous solution (5μl/eye, three or six times per day) were instilled into the right eyesfor 21 days. At 28 days after initiation, the peripheries of themeibomian gland orifices on the right upper eyelids were observed usinga slit-lamp and the telangiectasia score was determined.

(Results)

The results (the means of the telangiectasia scores) are shown in Table2.

TABLE 2 Telangiectasia score 7 days after 28 days after initiationinitiation (day 0 from start (day 21 from start of administration) ofadministration) Saline-administered group 5.3 4.3 1% clarithromycinaqueous 5.3 2.8 solution-administered group (instilled 3 times per day)1% clarithromycin aqueous 5.3 2.5 solution-administered group (instilled6 times per day)

(Discussion)

At seven days from the initiation (day 0 from the start ofadministration), no difference was recognized in the means of thetelangiectasia scores of each group, but 28 days after initiation (day21 from the start of administration), the telangiectasia score in thevicinity of the meibomian gland orifices in the 1% clarithromycinaqueous solution-administered group (instilled three or six times perday) was remarkably lower compared to the saline-administered group.

2. Test for Obstruction of Meibomian Gland Orifices by Feeding HR-ADDiet Using Hairless Mice

(Method for Preparation of Test Sample)

A 1% (w/v) clarithromycin test solution was prepared by the sameoperation as described in Pharmacological Test 1.

(Test Method)

Male Hos:HR-1 hairless mice at five weeks of age were divided into agroup of 6 fed a regular diet (CRF-1 diet, manufactured by OrientalYeast Co., Ltd.); and a group of 12 fed an HR-AD diet (manufactured byNosan Corporation), and the mice in each respective group were freelyallowed to feed the regular diet or HR-AD diet. On the 28th day afterthe start of the diets, meibomian gland orifices were observed using aslit-lamp and the number of obstructed orifices out of eight meibomiangland orifices of the center of the right upper eyelid were counted. Thepresence or absence of an obstruction of the meibomian gland orifice wasdetermined based on whether the meibomian gland orifice was in a cloudyand swollen state.

The 12 mice in the HR-AD diet group were further divided into asaline-administered group; and a 1% (w/v) clarithromycin aqueoussolution-administered group, and testing was carried out with six eyesin each group so as to minimize variations in the mean scores of thenumber of obstructed meibomian gland orifices in each group; from the29th day after starting the diets, saline (2 μl/eye, three times perday) or 1% (w/v) clarithromycin aqueous solution (2 μl/eye, three timesper day) were instilled for 14 days. At 42 days after starting the diet,meibomian gland orifices were observed using a slit-lamp and the numberof obstructed orifices out of eight meibomian gland orifices of thecenter of the right upper eyelid were counted.

(Results)

The results (the means of the number of obstructed orifice scores) areshown in Table 3.

TABLE 3 Number of obstructed meibomian gland orifices 28 days after 42days after starting feeding starting feeding (day 0 from start (day 14from start of administration) of administration) Non-treated group 0.81.0 (group fed a regular diet) Saline-administered group 5.3 4.5 1%clarithromycin aqueous 5.5 1.8 solution-administered group

(Discussion)

At 28 days from starting the diet (day 0 from starting theadministration), there was almost no difference in the number ofobstructed meibomian gland orifices between the saline-administeredgroup (fed by HR-AD diet) and the 1% (w/v) clarithromycin aqueoussolution-administered group (fed by HR-AD diet), but 42 days afterstarting the diet (14 days from starting administration), the number ofobstructed meibomian gland orifices was remarkably decreased, andmeibomian gland concretion was improved in the 1% (w/v) clarithromycinaqueous solution-administered group.

INDUSTRIAL APPLICABILITY

In the present invention, by using clarithromycin as an effectivecomponent, it is possible to treat or prevent MGD or meibomian glandconcretion.

1. A method for therapy of meibomian gland dysfunction that is acondition where a diffuse abnormality of the function of the meibomianglands is induced by various causes, the method comprisingadministration of clarithromycin to a subject in need thereof.
 2. Themethod according to claim 1, wherein clarithromycin is administered in adosage form of an ophthalmic solution or ophthalmic ointment.
 3. Themethod according to claim 1, wherein clarithromycin is administered in adosage form of an ophthalmic solution in an amount of from 0.0001 to 5%(w/v).
 4. The method according to claim 1, wherein clarithromycin isadministered in a dosage form of an ophthalmic solution in an amount offrom 0.01 to 3 (w/v).